DE2840591A1 - IMIDAZOLE DERIVATIVES - Google Patents

Description

RAN 4038/3

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Imidazole derivatives

The present invention relates to imidazole derivatives of the general formula

, 4

(O)

S CH X I

12 3 4
wherein R, R, R and R are each hydrogen or

1 2 3 4

R together with R and R together with R each have an additional carbon-carbon bond, η is the number 0 or 1, R is hydrogen

Green / 8.8.78

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or lower alkyl and X is optionally monosubstituted by lower alkyl 2-pyridyl radical, a

2-imidazolyl radical, a 2-imidazolinyl radical, a 2-thiazolyl radical, a 2-thiazolinyl radical, or a 4 (5) -imidazolyl radical which is optionally monosubstituted by lower alkyl, and their acid addition salts.

The term "lower alkyl" denotes straight-chain or branched, saturated, aliphatic hydrocarbon radicals with up to 7, preferably up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl.

Among the compounds according to the present invention those are preferred in which X is a 2-pyridyl radical which is optionally monosubstituted by lower alkyl. The methyl-substituted 2-pyridyl radical is particularly preferred. Among the alkyl-substituted 2-pyridyl radicals those with a 5- or 6-position methyl group are particularly preferred. R is preferably hydrogen. Farther are among the compounds according to the present

1 2

Finding those preferred in which R together with R

3 4

and R together with R each have an additional carbon-carbon bond mean and those in which η = 0.

The invention further relates to a process for the preparation of the compounds I and pharmaceutical preparations of that.

2 - [/ (5-Methyl-2-pyridyl) methyl / thio] -1H-naphth [2,3-d] imidazole are very particularly preferred and the 2 - [(2-pyridylmethyl) thio] -lH-naphth [2,3-d] imidazole.

Compounds of the general formula I and their acid addition salts can be produced according to the invention that

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'*'*> 2840531

a) for the preparation of compounds of the formula I in which η denotes the number O, a compound of the general formula

R ⁴

12 3 4
wherein R, R, R and R above and Y have the meaning given below,

with a compound of the general formula

R ⁵
!
Y ¹ - CH - X III

wherein R and X have the above and Y ^{1 has} the meaning given below,

converts, where one of Y and Y "is a mercapto group and the other means a leaving group, or

b) for the preparation of compounds of the formula I in which η denotes the number 1, a corresponding compound of Formula I, in which η denotes the number 0, oxidizes,

if desired, a mixture of diastereoisomers that may have been obtained into the diastereoisomeric racemates and / or a possibly obtained racemate into the two antipodes splits and / or a free base obtained in an acid addition salt and / or an acid addition salt obtained in the free base or converted into another acid addition salt.

According to a first embodiment of the invention Process is thus a compound of the general formula II with a compound of the general formula III implemented, where either the symbol Y in formula II is a mercapto group and the symbol Y 'in formula III is a departure

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group or the symbol Y in formula II is a leaving group and the symbol Y ¹ in formula III is a mercapto group. Leaving groups are, for example, halogen, in particular chlorine, bromine or iodine, or acid radicals, for example the radical of a strong organic sulfonic acid, for example an arylsulfonyloxy radical such as tosyloxy, or an alkylsulfonyloxy radical such as mesyloxy. Further examples of leaving groups are alkyl mercapto radicals such as methyl mercapto, or alkylsulfinyl radicals such as methylsulfinyl. The reaction of the compounds II and III is expediently carried out in the presence of a solvent or solvent mixture which is inert under the reaction conditions and, if appropriate, in the presence of a base. Suitable bases for this are in particular inorganic bases, such as sodium or potassium hydroxide, sodium or potassium hydride and the like, or organic bases, such as triethylamine or other tertiary amines.

Suitable solvents or solvent mixtures are primarily alcohols, such as ethanol, mixtures of Alcohols and water, ethers such as tetrahydrofuran, halogenated hydrocarbons such as methylene chloride or Chloroform. A preferred solvent is dimethylformamide.

The reaction temperature is within fairly wide limits variable; it will usually be between room temperature and the boiling point of the reaction mixture, with one preferably works at the boiling point of the reaction mixture. An expedient embodiment of the present aspect of the process consists in the fact that a compound of the formula II, in which Y is a mercapto group, first converted into an alkali derivative, for example by means of sodium hydroxide, whereupon the reaction with a compound of the formula III in which Y is the acid residue of a reactive ester. In a preferred embodiment, the reaction takes place in dimethylformamide in the absence of a base with heating.

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~ ^r ~ ⁴² 28A0591

In a further embodiment of the process according to the invention, a compound of the formula I in which η the number 0 means oxidized. In doing so, a sulfur atom is converted into the sulfinyl group, and you accordingly uses for this purpose oxidizing agents which are customary for such transfers, for example Peracids, such as m-chloroperbenzoic acid, hydrogen peroxide, Perester, sodium metaperiodate, selenium dioxide, manganese dioxide, etc. The oxidation is conveniently carried out in a sub the reaction conditions inert organic solvent, for example in a halogenated hydrocarbon, such as Methylene chloride, chloroform, dichloroethane and the like or in a hydrocarbon such as benzene and the like; when using hydrogen peroxide as oxy- dation agent can also be worked in water, acetic acid and the like. It is beneficial to use the oxidizer to be used in a slight excess compared to the product to be oxidized. With the present Embodiment of the inventive method is conveniently worked at room temperature or below.

Depending on the structure of the starting products and / or the selected embodiment of the method according to the invention certain compounds of the formula I can be used as optical isomers or as a racemate or, if they contain at least two asymmetric centers, as mixtures of diastereoisomers or mixtures of racemates are present. Obtained mixtures of diastereoisomers and mixtures of racemates can be based on Due to physical-chemical differences of the components are separated; Racemates can by known methods be split, for example by fractional crystallization of salts with optically active acids.

The compounds of the formula I are obtained depending on the process conditions and the starting materials used either as free bases or as acid addition salts. The free bases can by reaction with organic or

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inorganic acids are converted into corresponding salts, the use of such acids being preferred, which form therapeutically acceptable salts, for example hydrogen chloride, hydrogen bromide, phosphoric acid, Sulfuric acid, citric acid, acetic acid, succinic acid, maleic acid, p-toluenesulfonic acid and the like. the Acid addition salts of the compounds of the formula I can be converted into the corresponding free bases in a manner known per se or converted into other acid addition salts. The acid addition salts of compounds of the formula I in which η stands for the number 1 are not very stable in aqueous solution.

The imidazole derivatives of the formula I and their salts inhibit gastric acid secretion and the formation of stress-induced gastric ulcers.

The inhibition of gastric acid secretion can be determined by the following experiment: Dogs are tested according to the Heidenhain technique [described by Rudick, J.Semb, LS and Nyhas, LM; J. Surgical Research Ti 383-398 (1967)] separated part of the gastric fundus from the rest of the stomach in the form of a pocket. A steel cannula is sewn into the pocket and passed out through the abdominal wall. After the surgical wound has healed, the animals begin the experiment, which is carried out on awake dogs. The gastric secretion is stimulated by an infusion of 4-methylhistamine dihydrochloride (40 mg / kg per hour IV), a selective stimulator of the histamine H_ receptors. As soon as the volume and pH of the 15 minute fractions have constant values, the test substance is administered orally. The dose of the test substance is determined which causes an inhibition of the acid secretion produced by 4-methylhistamine by 60-80%.

For the 2 - [/ (5-methyl-2-pyridyl) methyl / thio] -lH-naphth [2,3-d] imidazole, which shows a DL ₅₀ of more than 8000 mg / kg po in the mouse, and .for 2- [(2-pyridylmethyl) thio] -lH-naphth [2,3-d] imidazole, which is found in mice

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n> 500 mg / kg p. ο. shows is 3 mg / kg p.o.

a DL, - _O of> 500 mg / kg p. ο. shows this dose is

The inhibition of the development of stress-induced gastric ulcers can be demonstrated by the following experiment are: Immediately after oral application of the test substance to female rats (weight 140-160 g), the animals (10 rats per dose) placed in a water bath (22.5 ° C; 7 cm high). After 6 hours this stressful situation leads to gastric ulcers in any untreated animal. After this defined time, the treated rats are killed and those without gastric ulcer were counted. The EDj. - the dose, in which 50% of the animals are protected against stress-induced gastric ulcers - is determined using the probit method.

In this test, the 2 - [/ (5-methyl-2-pyridylmethyl / thio] -lH-naphth [2,3-d] imidazole shows an ED_ of 31 mg / kg po and the 2 - [(2-pyridylmethyl) thio] -lH-naphth [2,3-d] imidazole an ED ₅₀ of 12 mg / kg po.

The compounds of the formula I can therefore be used as medicaments, for example for the treatment of gastric ulcers, in the form of pharmaceuticals Find preparations that use them or their therapeutically acceptable salts in a mixture with one for pharmaceutical, organic or inorganic suitable for enteral, percutaneous or parenteral administration inert carrier material such as water, gelatin, gum arabic, lactose, starch, magnesium stearate. Talk, contain vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form Form, e.g. as tablets, coated tablets, suppositories, capsules? in semi-solid form, e.g. as ointments? or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contained Auxiliaries, such as preservation, stabilization, network or Emulsifiers, salts to change the osmotic pressure or buffers. You can also do other therapeutic ones contain valuable substances.

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The dosage is based on individual requirements; when administered orally is usually one Daily dose of 100-400 mg and for intravenous administration a daily dose of 5-20 mg is preferred.

The starting products of the formulas II and III are generally known; if individual connections are not yet are described, they can without difficulty in analogy to those described for the known compounds Presentation methods are produced.

In the following examples, which illustrate the present invention but are not intended to limit its scope in any way, all temperatures are given in ^° C.

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example 1

In a 250 ml sulphonation flask with stirrer / thermometer, The condenser and the dropping funnel were 10.1 g of 1H-naphth [2,3-d] imidazol-2-thiol suspended in 100 ml of alcohol. A solution of 4.0 g of sodium hydroxide in 50 ml of water was then added dropwise closed, resulting in a clear solution. The mixture was then heated to boiling temperature, and 8.2 g of 2-chlorine thy 1-pyridine hydrochloride were added and allowed to reflux overnight. The reaction mixture was then evaporated, the residue taken up in 600 ml of ethyl acetate and 200 ml of water and washed the ethyl acetate phase twice with 200 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized once from ethyl acetate / petroleum ether and provided 2 - [(2-pyridylmethyl) thio] -1H-naphth [2,3-d] imidazole, melting point 165-167; the hydrochloride melts at 230-231 °.

Production of the raw materials :

125.0 g of 2,3-dihydroxynaphthalene were _{suspended in 3.5 1 of NH 3} (25% strength) and shaken at 240 ° / 30 bar N _{3 for} 60 hours. The suspension was suction filtered, washed with 1.5 l of water and then dissolved in 7 l of ethyl acetate. The ethyl acetate solution was extracted twice with 1 1 3N NaOH each time and twice with 1 1 H ₃ O each time, dried over Na ₃ SO ^, filtered through charcoal and the decolorized filtrate was evaporated in vacuo at 40 °. The residue was stirred for 1 hour at room temperature in 400 ml of acetonitrile, suction filtered and dried. 128 g of 2,3-diaminonaphthalene obtained in this way were suspended in 900 ml of ethanol. A solution of 51.0 g of KOH in 160 ml of water was added dropwise with vigorous stirring.

After stirring for 10 minutes at room temperature, 71.6 g of carbon disulfide were added dropwise. The reaction mixture was stirred for 1 hour at about 20 °, then further overnight at the boiling temperature. After the addition of 91.0 g KOH in 370 ml of water, everything went into solution. It is suction filtered through 50 g of charcoal and the filtrate is diluted with 900 ml of water. At 60-70 °

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At the internal temperature and with stirring, 295 ml of glacial acetic acid in 295 ml of water were added dropwise. Then was the suspension was stirred for a further 1 hour at the same temperature, then cooled in an ice bath and suction filtered. The residue was washed with 300 ml of water and then with 100 ml of ethanol. Obtained after drying in vacuo at 60 ° 158.0 g of crude product suspended in 600 ml of dioxane are stirred at about 20 ° for 1 hour and then suction filtered became. The precipitate was washed successively with 100 ml of dioxane and 300 ml of ether. One received after Drying in vacuo at 60 ° 148.1 g of 1H-naphth [2,3-d] -imidazole-2-thiol. M.p. 303-305 °.

120 g of 2-hydroxymethylpyridine were in 2 1 abs. benzene touched. At 0-5, 100 ml of thionyl chloride were slowly added dropwise and the reaction mixture was stirred overnight at approx. 20 °. It was cooled to 0-5 ° and suction filtered. The precipitate was dissolved in 1000 ml of hot ethanol, over Filtered charcoal and evaporated at 50. The residue was dissolved in 400 ml of acetonitrile and stirred at room temperature 1 Hour and sucks off the 2-chloromethylpyridine HCl. Melting point 121-123 °.

Example 2

9.4 g 2-C (2-pyridylmethyl) thio] -lH-naphth [2,3-d] imidazole suspended in 250 ml of methylene chloride. With vigorous stirring a solution of 6.7 g of m-chloroperbenzoic acid in 150 ml of methylene chloride was added dropwise while cooling with ice / methanol, and the mixture was stirred the mixture then for another 5-7 hours at 0-5. It was then washed three times with 100 ml of sodium bicarbonate solution, Washed neutral with twice 200 ml of Kochsalζ solution, over Dried sodium sulfate and evaporated in vacuo. The residue was recrystallized from 500 ml of toluene and provided 2 - [(2-pyridylmethyl) sulfinyl] -1 H -naphth [2,3-d] imidazole from a melting point of 145-146 °.

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Example 3

0.92 g of 2-chloro-1H-naphth [2,3-d] imidazole and 0.57 g 2-mercaptomethylpyridine were refluxed for 18 hours in 15 ml of ethanol and 4.5 ml of IN sodium hydroxide solution. . The reaction solution was mixed with 50 ml of water and extracted twice with a total of 50 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution washed, dried over magnesium sulfate and concentrated to dryness on a rotary evaporator. Crystallization from 50 ml of acetonitrile yielded 0.68 g of 2 - [(2-pyridylmethyl) thio] -1H-naphth [2,3-d] imidazole from the m.p. "169-170 °.

Manufacture of the raw material ;

16.2 g of 2-hydroxy-1H-naphth [2,3-d] imidazole were in 170 ml of phosphorus oxychloride heated to reflux for 3 hours = the reaction solution was concentrated, with water decomposed and made basic with ammonia. The suction filtered residue was chromatographed on 500 g of silica gel. Ethyl acetate eluted 2.5 g of 2-chloro-IH-naphth [2,3-d] imidazole Crystallization from methanol gave a product with a melting point 300 °.

Example 4

0.45 g of 2-methylthio-1H-naphth [2,3-d] imidazole and 0.65 g of 2-mercaptomethylpyrxdine were refluxed in 10 ml of ethanol for 40 hours. 10 ml of water were added to the homogeneous solution and the precipitate formed was filtered off. This gave 0.50 g of 2- [(2-Pyridy! Methyl) thio] -lH-naphth [2,3-d] imidazole mp "170 ° _o

Production of the raw material:

20.0 g of 1H-naphth [2,3-d] imidazol-2-thiol and 4.0 g of sodium hydroxide were dissolved in 150 ml of ethanol with 6.5 g of methyl

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iodide heated to reflux for 1 hour. The reaction solution was diluted with 500 ml of water and the precipitated product filtered off with suction. Crystallization from dioxane yielded 12.0 g 2-methylthio-1H-naphth [2,3-d] imidazole of m.p. 242-244 °.

Example 5

0.165 g of 2- (methylsulfinyl) -1H -naphth [2,3-d] imidazole and 0.090 g of 2-mercaptomethylpyridine were in 5 ml of ethanol and 0.72 ml IN sodium hydroxide solution heated to reflux for 1 hour. The reaction solution was concentrated and poured onto silica gel chromatographed. Ethyl acetate eluted 0.050 g of 2 - [(2-pyridylmethyl) thio] -lH-naphth [2,3-d] imidazole.

Manufacture of the raw material ;

4.3 g of 2- (methylthio) -lH-naphth [2,3-d] imidazole in 500 ml of methylene chloride was at 0-5 ° with a solution of 4.2 g of m-chloroperbenzoic acid in 100 ml of methylene chloride were added dropwise. The reaction solution became 90 Stirred for minutes at 0 °, twice with aqueous potassium bicarbonate solution and washed once with saturated sodium chloride solution, dried over magnesium sulfate and am Rotary evaporator concentrated. Crystallization from acetonitrile gave 2.3 g of 2- (methylsulfinyl) -1H-naphth [2,3-d] -imidazole from m.p. 194.

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Example 6

90, Og 1H-naphth [2,3-d] imidazol-2-thiol in 200 ml Dimethylformamide were heated to 95. 80.1 g of 2-chloromethyl-5-methylpyridine hydrochloride were added to the homogeneous solution added and held at 95 for 10 minutes. After cooling to room temperature, 1 liter of ether mixed in and sucked off. The residue was taken up in 2N potassium bicarbonate solution and added with a total of 2 l Extracted methylene chloride. The organic phases were

2_q washed with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated on a rotary evaporator. The residue was recrystallized from 2 l alcohol. 106 g of 2 - / [(5-methyl-2-pyridyl) methyl] thio / -lH-naphth [2,3-d] imidazole with a melting point of 185 ° -186 ° were obtained.

Preparation of the 2-chloromethyl -5-ynethylpyridine hydrochloride:

11.5 g of 2,5-dimethylpyridine-N-oxide in 5 ml of acetic acid were added dropwise to 18 ml of acetic anhydride warmed to 120. The reaction solution was still Boiled under reflux for 45 minutes, concentrated on a rotary evaporator and distilled at 8 mmHg / 115 °. One received 14.0 g of 2-acetoxymethyl-5-methylpyridine.

14.0 g of 2-acetoxymethyl-5-methylpyridine were in a solution of 4.5 g of sodium hydroxide in 150 ml of water Heated to reflux for 90 minutes. The cooled solution was saturated with sodium chloride and with a total of 100 ml Chloroform extracted. The organic phases were washed with saturated sodium chloride solution over magnesium sulfate dried and concentrated at 40/16 torr. The oil obtained distills at 12 ° / 8 mmHg. 8.7 g were obtained 2-hydroxymethyl-5-methylpyridine.

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8.7 g of 2-hydroxymethyl-5-methyl-pyridine were added dropwise to 18 ml at a reaction temperature of 0-10 ° Thionyl chloride given. The reaction solution was then Stirred for 15 hours at room temperature and then concentrated on a rotary evaporator. The residue was treated in alcohol with activated charcoal and crystallized from alcohol-ether. 11.5 g of 2-chloromethyl-5-methylpyridine hydrochloride were obtained from m.p. 145-146.

Example 7

8.1 g of 1H-naphth [2,3-d] imidazol-2-thiol in 80 ml of ethanol and 40 ml of water were mixed with 3.2 g of sodium hydroxide and 7.2 g of 2-chloromethyl-4-methyl-pyridine hydrochloride and heated to reflux for 2 hours. The reaction solution was concentrated and between water and ethyl acetate / tetrahydrofuran distributed. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness on a rotary evaporator. The oily residue turned off Toluene crystallizes. 6.5 g of 2 - / [(4-methyl-2-

pyridyl) methyl] thio / -lH-naphth [2,3-d] imidazole of m.p. 170-172 °.

Analogously, 2 - / [(6-methyl-2-pyridyl) methyl] thio / -lH-naphtht2,3-d] imidazole, 119-120 ° produced.

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Example 8

6.4 g of NaOH in 40 ml of water were added at 0 ° to 8 g of 1H-naphth [2,3-d] imidazol-2-thiol in 80 ml of ethanol and then, with stirring, 8.72 g of rac-2- (1-chloroethyl) pyridine added dropwise in 40 ml of ethanol. After refluxing for 12 hours, the solution was evaporated in vacuo and the residue is worked up again with ethyl acetate-water. From 11.5 g of crude product was obtained after Purification on silica gel and crystallization from ethyl acetate 6.0 g of rac-2- / ti- (2-pyridyl) ethyl] thio / -lH-naphth [2,3-d] -imidazole, smp. 129-133 °.

The optical resolution of the racemate was carried out using (+) or (-) - di-0,0 ¹ -p-toluoyl-tartaric acid (DITTA) in ethyl acetate-toluene (1: 1).

(-) (RR) DITTA salt with (+) base m.p. 142-143 °, [α] = + 93.7 ° (in methanol, c = 1.0)

(+) Base m.p. 136-137 °, [α] = + 413.8 ° (+) (SS) DITTA salt with (-) base m.p. 136-137 °, [cc] _D = -92.1 °

(-) Base m.p. 135.5-136.5 °, [a] _Q = -408.6 °

Example 9

10.0 g of 1H-naphth [2,3-d] imidazol-2-thiol and 9.6 g of 2-chloromethyl-5-ethyl-pyridine hydrochloride were in 200 ml Ethanol and 100 ml IN sodium hydroxide solution heated to reflux for 2 hours. The reaction solution was on a rotary evaporator concentrated, taken up in 2 50 ml of water and extracted three times with 100 ml of ethyl acetate. The organic Phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and dried to dryness constricted. Crystallization from acetonitrile gave 8.2 g of 2 - / [(5-ethyl-2-pyridyl) methyl] thio / -lH-naphth [2,3-d] -imidazole from m.p. 156-157 °.

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Example 10

To 4.09 g of 5,6,7,8-tetrahydro-1H-naphth [2,3-d] imidazole-2-thiol in 50 ml of ethanol were 2.24 g of KOH in 10 ml of water, then 3.28 g of 2-chloromethylpyridine. HCl in 20 ml Ethanol added. After refluxing for 12 hours, the solution was evaporated in vacuo and the worked Normal residue with ethyl acetate-water. The ethyl acetate phase, concentrated to approx. 50 ml and cooled to 0 ° yielded 4.8 g of crystals with a melting point of 95 ° -97 °, which were recrystallized from 50 ml of acetonitrile: 4.15 g of 5,6,7,8-tetrahydro-2 - [(2-pyridylmethyl) thio] -1H-naphth [2,3-d] -imidazole, M.p. 98-101 °.

Production of the raw material :

To a solution of 16.2 g of 5,6,7,8-tetrahydro-2,3-diaminonaphthalene in 100 ml of isopropanol and 20 ml of ethanol, 6.16 g of KOH were first dissolved in 20 ml of water at 0 °, then 7.3 ml of carbon disulfide were added dropwise. To

Boiling under reflux for 2 hours, the pH was adjusted to 3-4 with glacial acetic acid and the white crystals which had precipitated out sucked at 0 °. The crystals were dissolved in 200 ml of isopropanol, and the solution was refluxed for half an hour cooked, and sucked off at 0 °. 17.8 g of 5,6,7,8-tetrahydro-1H-naphth [2,3-d] imidazol-2-thiol were obtained, M.p. 282-289 °.

Example 11

3.2 g of 2 - / [(5-Ethy1-2-pyridyl) methyl] thio / -IH-naphth [2,3-d] imidazole were in 200 ml of methylene chloride at a reaction temperature of 0-5 ° dropwise with a Solution of 1.7 g of m-chloroperbenzoic acid in 50 ml of methylene chloride were added. The reaction solution was at 0 °

Stirred for 3 hours, then twice with aqueous potassium bicarbonate solution, washed once with saturated sodium chloride solution and then concentrated to dryness. The green one

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The residue was treated with activated charcoal in acetonitrile / methanol and crystallized from the same solvent mixture. 2.1 g of 2 - / [(5-ethyl-2-pyridyl) methyl] sulfinyl / -lH-naphth] 2,3-d] imidazole were obtained of m.p. 177 ° =

Example 12

1.1 g of 2-hydroxymethylthiazole were dissolved in 50 ml of chloroform dissolved and stirred with 0.82 ml of thionyl chloride for 2 hours, then refluxed for 30 minutes. To Evaporation in vacuo at 40, the residue was taken up in 20 ml of ethanol and the solution was evaporated again. the obtained crystals of chloromethylthiazole hydrochloride were mixed with a solution of 1.91 g of 1H-naphth [2,3-d] imidazole-2-thiol 50 ml of ethanol, 2.14 g of KOH and 10 ml of water are added and the mixture is refluxed for 2 hours. The solvent was removed in vacuo and the residue worked up with ethyl acetate-water. After two recrystallizations 1.3 g of 2 - [(2-thiazolylmethyl) thio] -lH-naphth [2,3-d] imidazole were obtained from acetonitrile, 153-157 °.

Example 13

1.0 g of 1H-naphth [2,3-d] imidazole-2-thiol and 0.8 g of 2-chloromethylimidazole hydrochloride were dissolved in 20 ml of dimethylformamide Heated to 90 ° for 1 1/2 hours. The resulting precipitate was filtered off and washed with a little acetonitrile and dissolved in 2N sodium bicarbonate solution. The aqueous phase was washed three times with 30 ml of ethyl acetate extracted. The organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate and then narrowed. The residue was recrystallized from 150 ml of acetonitrile. 150 mg of 2 - [(imidazol-2-y! Methyl) thio] -lH-naphth [2,3-d] imidazole were obtained, 172 °.

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Example 14

10.0 g of 1H-naphth [2,3-d] imidazol-2-thiol and 8.0 g 2-chloromethylimidazoline hydrochloride were in 50 ml Dimethylformamide heated to 90 ° for 3 hours. After cooling to room temperature, the mixture was diluted with 200 ml of toluene. The residue was filtered off with suction, washed well with toluene, and from 700 ml of methanol with the addition of 300 ml of ether crystallized. 10.3 g of 2 - [(2-imidazolin-2-ylmethyl) thio] -1H-naphth [2,3-d] imidazo1-dihydrochloride were obtained of m.p. 227-228 °.

Example 15

2.5 g of 2- (1-hydroxyethyl) thiazole were abs in 50 ml. Chloroform mixed with 2.38 g of thionyl chloride in 10 ml of chloroform at 0 °, and 1 hour at 0 °, 30 minutes at 20 ° and stirred under reflux for 1 hour. After removing the solvent in vacuo, the residue was dissolved in 20 ml Ethanol and the solution evaporated again. The mixture of 4.0 g of 1H-naphth- [2,3-d] imidazol-2-thiol, 80 ml of ethanol, 4.48 g of KOH and 40 ml of water were added and the mixture was refluxed for 12 hours. After evaporation in vacuo, the residue was taken up in 300 ml of water and extracted three times with 200 ml Methylene chloride. The organic phases, which had evaporated to dryness, crystallized from benzene. After two recrystallizations from benzene, 1.8 g of 2 - / [l- (2-thiazolyl) ethyl] thio / -lH-naphth [2,3-d] imidazole were obtained, M.p. 184-186 °.

Example 16

2.85 g of 5,6,7,8-tetrahydro-1H-naphth [2,3-d] imidazole-2-thiol were together with 50 ml of ethanol, 2.24 g of KOH, 10 ml of water and 2.5 g of 2-chloromethyl-5-methyl-pyridine for 12 hours boiled under reflux, then evaporated in vacuo and worked up with methylene chloride-water. From 4.8g residue

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was obtained after recrystallization from 80 ml of acetonitrile 3.78 g of 5,6,7,8-tetrahydro-2 - / [(5-methyl-2-pyridyl) methyl] -thio / -1H-naphth [2,3-d] imidazole from m.p. 135-136 °.

5,6,7,8-Tetrahydro-2 - / [1- (2-pyridyl) -ethyl] thio / -lH-naphth [2,3-d] imidazole was used analogously produced, m.p. 124-125 °.

Example 17

3.05 g of 2 - / [(5-methyl-2-pyridyl) methyl] thio / -lH-naphth [2,3-d] imidazole and 3.0 g of potassium carbonate were dissolved in 300 ml of methylene chloride at 0-5 with a solution of 1.725 g of m-chloroperbenzoic acid in 50 ml of methylene chloride were added. The mixture was then stirred at 0 for 30 minutes, then with aqueous potassium bicarbonate solution and saturated Washed brine, dried over magnesium sulfate

and evaporated at 40 ° / 16 torr. The residue was recrystallized twice from acetonitrile. 1.6 g of 2 - / [(5-methyl-2-pyridyl) methyl] sulfinyl / -lH-naphth [2,3-d] -imidazole were obtained from m.p. 181

5,6,7,8-Tetrahydro-2 - [(2-pyridy! Methyl) -sulfenyl] -IH-naphth [2,3-d] imidazole, M.p. 155-156 °.

Example 18

8.0 g of 1H-naphth [2,3-d] imidazol-2-thiol were in 20 ml of dimethylformamide at 90 ° with 6.7 g of 4 = chloromethyl-5-

methyl imidazole hydrochloride added. After 10 minutes the mixture was cooled to room temperature and ether was added. The precipitate was filtered off with suction and taken from water-ethanol recrystallized. 6.5 g of 2 - / [(5-methylimidazol-4-yl) methyl] thio / -lH-naphth [2,3-d] imidazole dihydrochloride were obtained

from m.p. 265-267 °.

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Example 19

To 6.2 g of 5,6,7,8-tetrahydro-2 - / [1- (2-pyridyl) ethyl / -thio / -lH-naphth [2,3-d] imidazole in 50 ml of methylene chloride were at 0 35 ml of 10% solution of m-chloroperbenzoic acid added dropwise. After 3 hours of stirring at 0 °, the precipitated material was filtered off with suction, slurried with acetonitrile, sucked again and washed with ether, then with petroleum ether. 2.7 g of 5,6,7,8-tetrahydro-2 - / [1- (2-pyridyl) ethyl] sulfinyl / -lH-naphth [2,3- d] imidazole, m.p. 152-153 °.

The following were produced in the same way:

5,6,7,8-Tetrahydro-2 - / [(5-methyl-2-pyridyl) methyl] -sulfinyl / -lH-naphth [2,3-d] imidazole, Mp. 188-189 °, 2 - / [1- (2-pyridyl) ethyl] sulfinyl / -lH-naphth [2,3-d] imidazole, 172-173 °.

Example A Tablets having the following composition are prepared;

2- / [(5-Methyl-2-pyridyl) methyl] thio / -lH-naphth [2,3-d] imidazole 50.0 mg

Lactose powder, 100.0 mg

White corn starch 48.0 mg

Magnesium stearate 2.0 mg

200.0 mg

The mixture of finely ground active ingredient, lactose and part of the corn starch is made with a paste Water and a second part of the corn starch kneaded, granulated, dried and sieved. The granules will then first mixed with the rest of the corn starch and then with the magnesium stearate. The mixture turns into tablets too 200 mg pressed.

909813/0974

Example B.
Tablets are made with the following composition:

2 - [(2-pyridylmethyl) thio] -1 H -naphth

[2,3-d] imidazole 100.0 mg

Lactose powder, 150.0 mg

White corn starch 145.0 mg

Magnesium stearate 5.0 mg

400.0 mg

The mixture of finely ground active ingredient, lactose and part of the corn starch is kneaded with a paste of water and a second part of the corn starch,
granulated, dried and sieved. The granules are first mixed with the rest of the corn starch and then with the magnesium stearate. The mixture is compressed into tablets of 400 mg each.

90981 3/0974

Claims (1)

Claims , Iy Process for the preparation of imidazole derivatives of the general formula S GH X 12 3 4
wherein R, R, R and R are each hydrogen or 1 2 3 4 R together with R and R together with R each have an additional carbon-carbon bond, η is the number 0 or 1, R is hydrogen or lower alkyl and X is optionally 2-pyridyl radical monosubstituted by lower alkyl, a 2-imidazolyl- radical, a 2-imidazolinyl radical, a 2-thiazolyl radical, a 2-thiazolinyl radical, or a 4 (5) -imidazolyl radical optionally monosubstituted by lower alkyl,
characterized in that one a) for the preparation of compounds of the formula I in which η denotes the number 0, a compound of the general formula 909813/0974 Original inspected 12 3 4
wherein R, R, R and R are above and Y are below Have given meaning, with a compound of the general formula R ⁵ y - gh - χ in wherein R and X have the above and Y 'have the meaning given below, converts, where one of Y and Y 'is a mercapto group and the other means a leaving group, or b) for the preparation of a compound of the formula I in which η is the number 1, a corresponding compound of Formula I, in which η is the number .0, oxidizes, if desired, any. obtained diastereoisomer mixture into the diastereoisomeric racemates and / or a possibly obtained racemate into the two antipodes splits and / or, if desired, a free base obtained into an acid addition salt and / or a obtained one Acid addition salt into the free base or into another Acid addition salt transferred. 2. The method according to claim 1, characterized in that X is an optionally monosubstituted by lower alkyl 2-pyridyl radical, a 2-imidazolyl radical, a 2-imidazolinyl radical, a 2 = Means thiazolyl radical or a 2-thiazolinyl radical. 3. The method according to claim 2, characterized in that that X is a 2-pyridyl radical which is optionally monosubstituted by lower alkyl 4. The method according to claim 3, characterized in that that X denotes a methyl-substituted 2-pyridyl radical. 5. The method according to claim 4, characterized in that the methyl group is 5- or 6-position. 909813/0974 6. Process according to claims 1 to 5, characterized in that R is hydrogen. 7. The method according to claims 1 to 6, characterized in that η = O. 8. The method according to claims 1 to 7, characterized 1 2 3 marked that R together with R and R together with 4th
R each represent an additional carbon-carbon bond. 9. The method according to claim 1, characterized in that 2 - / [(5-methyl-2-pyridyl) methyl] thio / -lH-naphth [2,3-d] imidazole or an acid addition salt thereof. 10. The method according to claim 1-, characterized in that 2 - [(2-pyridylmethyl) thio] -lH-naphth [2,3-d] imidazole or an acid addition salt thereof. 909813 /: ■■ ·· 7 4 11. Process for the production of pharmaceutical preparations / characterized in that one is an imidazole derivative the general formula I defined in claim 1 or an acid addition salt thereof as an active ingredient with non-toxic, inert, inert ones which are customary in such preparations, which are suitable for therapeutic administration solid and / or liquid carriers and / or excipients and optionally one or more other active ingredients mixed. 098 13/0974 '* "' 28A0591 12. Pharmaceutical preparations containing an imldazole derivative of the general formula I defined in claim 1 or an acid addition salt thereof. 909813/0974 13 ο Imidazole derivatives of the general formula
, 4 (O) _ R ⁵ ViI © —CH X I 12 3 4
wherein R, R, R and R * are each hydrogen or 1 2 3 4 R together with R and R together with R an additional carbon-carbon bond each, η the number O or 1, R hydrogen
or lower alkyl and X is optionally
2-pyridyl radical monosubstituted by lower alkyl, a 2-imidazolyl radical / a 2-imidazolinyl radical, a 2-thiazolyl radical, a 2-thiazolinyl radical, or a 4 (5) -imidazolyl radical which is optionally monosubstituted by lower alkyl,
and their acid addition salts " 14. Compounds according to claim 13, wherein X is an optionally monosubstituted by lower alkyl
2-pyridyl radical, a 2-imidazolyl radical, a 2-imidazolinyl radical, a 2-thiazolyl radical or means a 2-thiazolinyl radical « 15. Compounds according to claim 14, wherein X is an optionally 2 = pyridyl radical monosubstituted by lower alkyl. 16. Compounds according to claim 15, wherein X is a methyl-substituted 2-pyridyl radical. 909813/0974 17. Compounds according to claim 16, wherein the methyl group 5 or 6 positions. 18. Compounds according to any one of claims 13 to 17, wherein R is hydrogen. 19. Compounds according to any one of claims 13 to 18, wherein η = O. 24. Compounds according to any one of claims 13 to 19, 1 2 3 4 where R together with R and R together with R each represent an additional carbon-carbon bond. 21. 2 - / [(5-Methyl-2-pyridyl) methyl-thio / -1H-naphth [2,3-d] imidazole and its acid addition salts. 22. 2 - [(2-Pyridylmethyl) thio] -1H -naphth [2,3-d] imidazole and its acid addition salts. 909813/0974